Process for the synthesis of 1,3-diols

ABSTRACT

An improved process for the preparation of cis-1,3-diols is described where a beta hydroxy ketone is treated with a trialkylborane or dialkylalkoxyborane or a mixture of a trialkylborane and a dialkylalkoxyborane followed by recovery and reuse of the alkylborane species to convert additional beta hydroxy ketone to the cis-1,3-diol.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a process for preparingcis-1,3-diols. More particularly, the present invention relates to theuse and subsequent recovery and reuse of a trialkylborane ordialkylalkoxyborane or a mixture of a trialkylborane and adialkylalkoxyborane in the reduction of a beta-hydroxy ketone to obtaina cis-1,3-diol. Additionally, the present invention relates to the useof a synergistic combination of a trialkylborane and adialkylalkoxyborane in the reduction of a beta-hydroxy ketone to obtaina cis-1,3-diol.

[0002] The use of trialkylboranes or dialkylalkoxyboranes in thestereoselective reduction of 1,3-keto alcohols to the correspondingsyn-1,3-diols has been widely described in the literature. This methodhas given high stereoselectivity without using extraordinarily difficultconditions (Brower P. L., Butler D. E., Deering C. F., Le T. V., MillarA., Nanninga T. N., and Roth B., Tetrahedron Lett., 1992;33:2279;Narasaka K., and Pai F. C., Tetrahedron, 1984;40:2233; Chen K. M.,Hardtmann G. E., Prasad K., Repic O., and Shapiro M. J., TetrahedronLett., 1987;28:155; Chen K. M., Gunderson K. G., Hardtmann G. E., PrasadK., Repic O., and Shapiro M. J., Chem. Lett., 1987:1923). There seems tobe general acceptance of the formation of a borate ester from either thetrialkyl or dialkylalkoxyboranes which is said to form a cyclic chelate(Narasaka K. and Pai F. C., Tetrahedron, 1984;40:2233; Chen K. M.,Hardtmann G. E., Prasad K., Repic O., and Shapiro M. J., TetrahedronLett., 1987;28:155; Chen K. M., Gunderson K. G., Hardtmann G. E., PrasadK., Repic O., and Shapiro M. J., Chem. Lett., 1987:1923; see for examplePaterson I., Cumming J. G., and Smith J. D., Tetrahedron Lett.,1994;35:3405). Axial delivery of a hydride to the complex then leadspredominately to the syn-product which can be hydrolyzed to the diol.The diols are valued as intermediates for the preparation of, forexample, HMG-CoA reductase inhibitors which are useful hypolipidemic andhypocholesterolemic agents. This is a widely used method of preparationof such agents (U.S. Pat. Nos. 4,645,854, 5,354,772, 5,155,251, and4,970,313).

[0003] Many procedures in the literature, describe the work-up of thereaction with hydrogen peroxide (U.S. Pat. No. 4,645,854 and 4,970,313).This results in the destruction of active alkylborane species. Someprocedures describe the repeated distillation with methanol and an acid(U.S. Pat. No. 5,354,772 and 5,155,251). This also dilutes andeventually destroys the active alkylborane species. We have surprisinglyand unexpectedly found that by performing the reduction and workup witha minimal amount of acid, and keeping the distillate streams separated,that the initial distillate can be recovered and reused to obtain verygood selectivity in subsequent reductions.

[0004] Thus, the present process offers significant advantages over theprior art processes. For example, the cost of additional alkylborane iseliminated for each batch in which the distillate stream is recycled.Additionally, since alkylboranes are hazardous, they must be destroyedprior to being disposed. The present process minimizes this expensiveand time-consuming procedure. Moreover, it is especially surprising thatvery good selectivity in the reductions is obtained using recoveredalkylboranes.

[0005] Finally, we have also surprisingly and unexpectedly found that acombination of a trialkylborane and a dialkylalkoxyborane is synergisticin selectively reducing a beta-hydroxy ketone to obtain a cis-1,3-diol.

SUMMARY OF THE INVENTION

[0006] Accordingly, a first aspect of the present invention is a processfor the preparation of a compound of Formula I

[0007] wherein R is alkyl,

[0008] NC—CH₂—,

[0009] PG—O—CH₂— wherein PG is a protecting group,

[0010] —CH₂—CO₂R⁶ wherein R⁶ is alkyl;

[0011] which comprises:

[0012] Step (a) treating a compound of Formula II

[0013]  wherein R and R¹ are as defined above with a trialkylborane ordialkylalkoxyborane or a mixture of a trialkylborane and adialkylalkoxyborane in a solvent;

[0014] Step (b) adding an alkali metal hydride at about −110° C. toabout −50° C.;

[0015] Step (c) concentrating the reaction by distillation to afford acompound of Formula I and a distillate containing alkylborane species;and

[0016] Step (d) treating additional compound of Formula II or III withthe distillate from Step (c) containing recovered alkylborane speciesand repeating Steps (b) and (c) as desired to afford additional compoundof Formula I.

[0017] A second aspect of the present invention is a process for thepreparation of a compound of Formula I

[0018] wherein R is alkyl,

[0019] NC—CH₂—,

[0020] PG—O—CH₂— wherein PG is a protecting group,

[0021] —CH₂—CO₂R⁶ wherein R⁶ is alkyl;

[0022] which comprises:

[0023] Step (a) treating a compound of Formula II

[0024]  wherein R and R¹ are as defined above with a synergisticcombination of a trialkylborane and a dialkylalkoxyborane in a solvent;and

[0025] Step (b) adding an alkali metal hydride at about −110° C. toabout −50° C. to afford a compound of Formula I.

[0026] A third aspect of the present invention is a synergisticcombination comprising a trialkylborane and a dialkylalkoxyborane.

DETAILED DESCRIPTION OF THE INVENTION

[0027] In this invention the term “alkyl” means a straight or branchedhydrocarbon radical having from 1 to 10 carbon atoms and includes, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary-butyl,isobutyl, tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, and the like.

[0028] “PG” means a protecting group used for protecting an alcoholmoiety such as, for example, benzyl and the like. Additional examples ofprotecting groups for an alcohol moiety are disclosed at Chapter 2 inGreene T. W., “Protective Groups in Organic Synthesis”, John Wiley &Sons, Inc., 1981.

[0029] “Alkali metal” is a metal in Group IA of the periodic table andincludes, for example, lithium, sodium, potassium, and the like.

[0030] “Alkaline-earth metal” is a metal in Group IIA of the periodictable and includes, for example, calcium, barium, strontium, and thelike.

[0031] “Alkali metal hydride” includes, for example, sodium borohydride,zinc borohydride, lithium borohydride, lithium aluminum hydride, and thelike.

[0032] “Alkylborane species” means a mono, di- or trialkylborane wherethe mono or dialkylborane is further substituted by hydrido or alkoxy asdefined hereinafter or a dimeric alkylborane species.

[0033] “Alkoxy” means O-alkyl as defined above for alkyl.

[0034] As previously described, the compounds of Formula I are eitheruseful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme Areductase (HMG CoA reductase) or are useful as intermediates to prepareHMG CoA reductase inhibitors.

[0035] Thus, the present process can be used to prepare various HMG CoAreductase inhibitors containing a cis-1,3-diol moiety. For example,atorvastatin disclosed and described in U.S. Pat. Nos. 4,681,893 and5,273,995; fluvastatin disclosed and described in U.S. Pat. No.5,354,772; bervastatin disclosed and described in U.S. Pat. No.5,082,859; cerivastatin disclosed and described in U.S. Pat. No.5,177,080; NK-LO4 disclosed and described in U.S. Pat. No. 5,011,930;dalvastatin disclosed and described in U.S. Pat. No. 4,863,957;glenvastatin disclosed and described in U.S. Pat. No. 4,925,852;erythro-7-[5-(2,2-dimethyl-butyryloxymethyl)-4-(4-fluorophenyl)-2,6-diisopropylpyridin-3-yl]-3,5-dihydroxy-6(E)-heptenoicmethyl ester disclosed and described in U.S. Pat. Nos. 5,006,530,5,169,857, and 5,401,746;7,7′-[2-(dimethylamino)-4-(4-fluorophenyl)-6-isopropylpyridine-3,5-diyl]bis[erythro-(E)-3,5-dihydroxy-6-heptenoic acid methyl ester disclosed anddiscribed in U.S. Pat. No. 5,145,857;7-[6-cyclopropyl-4-(4-fluorophenyl)-2-(4-methoxyphenyl)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoicacid sodium salt disclosed and described in U.S. Pat. No. 5,026,708;(E)-7-[4-(4-fluorophenyl)-2-isopropylquinolin-3-yl]-3,5-dihydroxy-6-heptenoicacid δ-lactone disclosed and described in U.S. Pat. Nos. 5,011,930,5,102,888, and 5,185,328;trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-6,6-dimethyl-4-(N-phenyl-carbamoyloxy)-1-cyclohexenyl]vinyl]-4-hydroxytetrahydropyran-2-onedisclosed and described in U.S. Pat. No. 5,001,144;erythro-(E)-7-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]-3,5-dihydroxy-6-heptenoicacid sodium salt disclosed and described in U.S. Pat. No. 4,863,957;(E)-trans-6-[2-[2-(4-fluoro-3,5-dimethylphenyl)-4-hydroxy-6,6-dimethyl-1-cyclohexenyl]vinyl]-4-hydroxytetrahydropyran-2-onedisclosed and described in U.S. Pat. No. 4,900,754; ethylE-(3R,5S)-7-[4′-fluoro-3,3′,5-trimethyl(1,1′)biphenyl-2-yl]-3,5-dihydroxy-6-heptenoatedisclosed and described in U.S. Pat. No. 4,567,289;3(R),5(S)-dihydroxy-7-[4-(4-fluorophenyl)-1-isopropyl-3-phenyl-1H-pyrazol-5-yl]hept-6(E)-enoicacid disclosed and described in U.S. Pat. No. 4,613,610; and(3R,5S)-BMY-21950 disclosed and described in U.S. Pat. No. 4,897,490 canbe obtained using the present process. All of the aforementioned U.S.patents are herein incorporated by reference.

[0036] The process of the present invention in its first aspect is animproved, economical, and commercially feasible method for preparing acompound of Formula I. The process of the present invention in its firstaspect is outlined in Scheme 1.

[0037] Thus, a compound of Formula II wherein R is alkyl,

[0038] NC—CH₂—,

[0039] PG—O—CH₂— wherein PG is a protecting group,

[0040] or a compound of Formula III wherein R and R¹ are as definedabove is treated with about 0.1 to about 2.0 molecular equivalents of atrialkylborane such as, for example, triethylborane, tripropylborane,tri n-butylborane, tri sec-butylborane and the like or adialkylalkoxyborane such as, for example, dimethylmethoxyborane,dimethylethoxyborane, dimethylisopropoxyborane, diethylmethoxyborane,diethylethoxyborane, diethylisopropoxyborane, diisopropylmethoxyborane,diisopropylethoxyborane, diisopropylisopropoxyborane, and the like or amixture of a trialkylborane and a dialkylalkoxyborane as describedpreviously, followed by the stereoselective reduction with about 1molecular equivalent of an alkali metal hydride such as, for example,sodium borohydride, zinc borohydride, lithium borohydride, lithiumaluminum hydride, and the like; in a solvent such as a hydrocarbon, forexample hexane, toluene, cyclohexane and the like; an alkanol, forexample methanol, ethanol, isopropanol and the like; or an ether, forexample diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, triglyme(triethylene glycol dimethyl ether) and the like, or mixtures thereof ata temperature of about −110° C. to about −50° C. to afford afterconcentration by distillation a compound of Formula I. Additionalcompound of Formula II or III is subsequently treated with thedistillate obtained by vacuum distillation from the first run followedby stereoselective reduction carried out as described above to afford asecond batch of a compound of Formula I. Thus, recovered quantities ofthe alkylborane species can be used to convert additional quantities ofa compound of Formula II or III to a compound of Formula I. Thisprocedure using recovered alkylborane species can be repeated as desiredto obtain additional quantities of a compound of Formula I.

[0041] Preferably, the reaction is carried out with about 1.2 to 0.8molecular equivalents of triethylborane or diethylmethoxyborane or amixture of a trialkylborane and a dialkylalkoxyborane as describedpreviously in a solvent, preferably a mixture of tetrahydrofuran andmethanol, at a ratio of about 8 volumes of tetrahydrofuran to one volumeof methanol. This is followed by the addition of about one molecularequivalent of sodium borohydride at about −110° C. to about −50° C.,preferably at −80° C., followed by stirring for about 30 minutes toabout 3 hours. Under these preferred conditions, greater than 90% of acompound of Formula I is produced in the desired stereochemicalconformation.

[0042] Preferably, the present process is used to prepare[R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate which isused as an intermediate to prepare atorvastatin. Compounds of Formula IIor III are either known or capable of being prepared by methods known inthe art.

[0043] The process of the present invention in its second aspect is animproved, economical, and commercially feasible method for preparing acompound of Formula I as previously outlined in Scheme 1.

[0044] In this aspect of the invention, applicants have found that acombination of a trialkylborane and a dialkylalkoxyborane surprisinglyand unexpectedly is synergistic in selectively affording the desiredcis-1,3-diol over the undesired trans-1,3-diol compared to the use ofeither a trialkylborane or a dialkylalkoxyborane alone. The synergisticcombination comprises about 1% to 99% by weight of a trialkylborane andabout 99% to 1% by weight of a dialkylalkoxyborane; preferably, acombination of about 90% by weight of a trialkylborane and 10% by weightof a dialkylalkoxyborane. This synergistic combination is of particularadvantage since it does not require a stir time of the alkylboranespecies with the hydroxyketone at ambient temperature before reduction.The conditions and solvents for carrying out the reaction with asynergistic combination of a trialkylborane and a dialkylborane are aspreviously described above.

[0045] Thus, for example, in the preparation of[R-(R*,R*)]1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate when nopre-stir is used, triethylborane affords a 5 to 10:1 (cis:trans)mixture. When diethylmethoxyborane is used in place of triethylborane, a5 to 10:1 (cis:trans) mixture is obtained. When a combination of 10% byweight of diethylmethoxyborane and 90% by weight of triethylborane isused, typically a greater than 30:1 (cis:trans) mixture is obtained.This synergistic effect of combining a dialkylalkoxyborane and atrialkylborane could not have been predicted based on the use of eitherreagent alone or literature precedent.

[0046] The following examples are illustrative to show the presentprocesses and to show the usefulness in the preparation of (4R-Cis)1,1-dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate whichis an intermediate prepared from a 1,3-diol of the present process thatcan be converted to atorvastatin([R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, calcium salt (2:1)) (crystalline Form I) which is useful as ahypolipidemic and hypocholesterolemic agent.

EXAMPLE 1 (4R-Cis)1,1-Dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate

[0047] Step (1): Preparation of 5R 1,1-Dimethylethyl6-cyano-5-hydroxy-3-oxohexanoate

[0048] To a vessel containing 265 kg of 16.8% n-butyllithium is added amixture of 80 kg of diisopropylamine in 80 L of tetrahydrofuranmaintaining the temperature at less than 20° C. The solution is cooledto −55° C., and 85 kg of tert-butyl acetate is added maintaining thetemperature at −50°±5° C. A solution of 25 kg of R4-cyano-3-hydroxybutanoic acid ethyl ester in 55 L of tetrahydrofuran isthen added, and the temperature is allowed to warm to −20° C. for atleast 20 minutes. The solution is then quenched by transferring toaqueous hydrochloric acid. The organic layer is separated and theaqueous layer re-extracted with ethyl acetate. The combined organiclayers are concentrated by vacuum distillation to afford crude 5R1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate.

[0049] Step (2): Preparation of [R-(R*,R*)]-1,1-Dimethylethyl6-cyano-3,5-dihydroxyhexanoate

[0050] Method A: Using Triethylborane

[0051] Step (a):

[0052] Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate(about 150 moles) from Step (1) is dissolved in 325 L of tetrahydrofurancontaining about 20 kg of triethylborane, stirred for about 2 hours atroom temperature, cooled to −75° C.±20° C. and diluted with 25 L ofmethanol and 8 kg of acetic acid. Sodium borohydride (8 kg) as asolution in methanol and aqueous sodium hydroxide is added slowly. Afterthe addition, the reaction mixture is warmed to 0° C.±25° C. Thereaction mixture is optionally quenched by the addition of 3 kg ofacetic acid and 10 L of methanol and concentrated by vacuumdistillation, saving the distillate. The residue is dissolved inmethanol and acetic acid, optionally diluted with water, andconcentrated by vacuum distillation, keeping this distillate separatefrom the first one. The residue is dissolved in methanol andconcentrated by vacuum distillation. The residue is dissolved in amixture of water and ethyl acetate, and the aqueous layer separated. Theorganic layer is concentrated by vacuum distillation. The residue isdissolved in methanol and acetic acid and concentrated by vacuumdistillation. The residue is dissolved in ethyl acetate and concentratedby vacuum distillation affording crude [R-(R*,R*)]-1,1-dimethylethyl6-cyano-3,5-dihydroxyhexanoate.

[0053] The cis:trans ratio was about 30:1 as measured after conversionto (4R cis and trans)1,1-dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate according to theprocedure described herein in Step 3.

[0054] Step (b): Reusing Recovered Triethylborane

[0055] Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate(about 150 moles) from Step (1) is dissolved in the first distillatefrom Step (a) along with 50 L of tetrahydrofuran, cooled to −75° C.±20°C., and optionally diluted with 25 L of methanol, and 10 kg of aceticacid. Sodium borohydride (8 kg) as a solution in methanol and aqueoussodium hydroxide is added slowly. After the addition, the reactionmixture is warmed to 0° C.±25° C. The reaction mixture is quenched bythe addition of 10 kg of acetic acid and 20 L of methanol andconcentrated by vacuum distillation. The residue is dissolved inmethanol and acetic acid, optionally diluted with water, andconcentrated by vacuum distillation. The residue is dissolved inmethanol and concentrated by vacuum distillation. The residue isdissolved in a mixture of water and ethyl acetate, and the aqueous layerseparated. The organic layer is concentrated by vacuum distillation. Theresidue is dissolved in methanol and acetic acid and concentrated byvacuum distillation. The residue is dissolved in ethyl acetate andconcentrated by vacuum distillation affording crude[R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.

[0056] The cis:trans ratio was about 40:1 as measured after conversionto (4R cis and trans) 1,1-dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate according to theprocedure described herein in Step 3.

[0057] Method B: Using Triethylborane

[0058] Step (a):

[0059] Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate(about 130 mmoles) from Step (1) is dissolved in 100 mL 1 Mtriethylborane in THF and 65 mL tetrahydrofuran, stirred for about 2hours at room temperature, then cooled to −75° C.±20° C., and dilutedwith 25 mL methanol. Sodium borohydride (6 g) as a solution in triglyme(75 mL) is added slowly. After the addition, the reaction mixture iswarmed to 20° C. to 25° C. The reaction mixture is quenched by theaddition of 20 mL methanol and 8 g acetic acid and concentrated byvacuum distillation—saving the distillate. The residue is diluted with100 mL water and 200 mL ethyl acetate, agitated, and the phasesseparated. The organic layer is concentrated by vacuumdistillation—keeping this distillate separate from the first one. Theresidue is dissolved in 200 mL methanol and 10 mL acetic acid andconcentrated by vacuum distillation. The residue is dissolved in 200 mLmethanol and concentrated by vacuum distillation. The residue isdissolved in 200 mL methanol and concentrated by vacuum distillation.The residue is dissolved in ethyl acetate and concentrated by vacuumdistillation resulting in crude [R-(R*,R*)]-1,1-dimethylethyl6-cyano-3,5-dihydroxyhexanoate.

[0060] The cis:trans ratio was about 20:1 as measured after conversionto (4R cis and trans) 1,1-dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate according to theprocedure described herein in Step 3.

[0061] Step (b): Reusing Recovered Triethylborane

[0062] Crude 5R1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about130 mmoles) from Step (1) is dissolved in the first distillate from theabove Step (a) mixture and cooled to −75° C.±20° C. Sodium borohydride(6 g) as a solution in 75 mL triglyme is added slowly. After theaddition, the reaction mixture is warmed to 25° C. The reaction mixtureis quenched by the addition of 8 g acetic acid (and optionally 20 mLmethanol) and concentrated by vacuum distillation—saving the distillate.The residue is dissolved in a mixture of water (100 mL) and ethylacetate (200 mL), the layers separated, and the organic layer isconcentrated by vacuum distillation. The residue is dissolved with 200mL methanol and 10 mL acetic acid and concentrated by vacuumdistillation. The residue is dissolved with 200 mL methanol andconcentrated by vacuum distillation. The residue is dissolved with 200mL methanol and concentrated by vacuum distillation. The residue isdissolved in ethyl acetate and concentrated by vacuum distillationresulting in crude [R-(R*,R*)]-1,1-dimethylethyl6-cyano-3,5-dihydroxyhexanoate.

[0063] The cis:trans ratio was about 30:1 as measured after conversionto (4R cis and trans) 1,1-dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate according to theprocedure described herein in Step 3.

[0064] Step (c): Reusing Recovered Triethylborane

[0065] Following the procedure of the previous Step (b) crude5R-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 130 mmoles)from Step (1) is reacted with recovered triethylborane from Step (b) toafford crude [R-(R* ,R*)]-1,1-dimethylethyl6-cyano-3,5-dihydroxyhexanoate.

[0066] The cis:trans ratio was about 30:1 as measured after conversionto (4R cis and trans) 1,1-dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate according to theprocedure described herein in Step 3.

[0067] Method C: Using Diethylmethoxyborane

[0068] Step (a):

[0069] Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate(about 150 mmoles) is dissolved by adding 22 mL diethylmethoxyborane and200 mL tetrahydrofuran. The solution is stirred for about 2 hours atroom temperature, then cooled to −70° C. to −75° C., and further dilutedwith 25 mL methanol. Sodium borohydride (6 g) as a solution in triglyme(75 mL) is added slowly at between −65° C. to −75° C. After theaddition, the reaction mixture is warmed to 15° C. to 25° C., quenchedby the addition of acetic acid and concentrated by vacuumdistillation—keeping this distillate. The residue is diluted withmethanol and concentrated by vacuum distillation—keeping this distillateand all subsequent ones separate from the first one. The residue isdissolved in a mixture of water and ethyl acetate, the layers separated,and the organic layer is concentrated by vacuum distillation. Theresidue is dissolved in methanol and acetic acid and concentrated byvacuum distillation. The residue is dissolved in ethyl acetate andconcentrated by vacuum distillation resulting in crude[R(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.

[0070] The cis:trans ratio was about 35:1 as measured after conversionto (4R cis and trans) 1,1-dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate according to theprocedure described herein in Step 3.

[0071] Step (b): Reusing Recovered Diethylmethoxyborane

[0072] Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate(about 150 mmoles) is dissolved in the first distillate from the abovemixture, allowed to stir at room temperature for about 2 hours, andcooled to about −70° C. Sodium borohydride (6 g) as a solution in 75 mLtriglyme is added slowly at between −65° C. to −75° C. After theaddition, the reaction mixture is warmed to 15° C. to 25° C., quenchedby the addition of acetic acid and concentrated by vacuum distillation.The residue is diluted with methanol and concentrated by vacuumdistillation. The residue is dissolved in a mixture of water and ethylacetate, the layers separated, and the organic layer is concentrated byvacuum distillation. The residue is dissolved with methanol and aceticacid and concentrated by vacuum distillation. The residue is dissolvedin ethyl acetate and concentrated by vacuum distillation resulting incrude [R(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.

[0073] The cis:trans ratio was about 25:1 as measured after conversionto (4R cis and trans) 1,1-dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate according to theprocedure described herein in Step 3.

[0074] Method D: Using a Mixture of Diethylmethoxyborane andTriethylborane

[0075] Step (a):

[0076] Crude 5R 1,1-Dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate(about 150 mmoles) is dissolved in 170 mL tetrahydrofuran. The solutionis cooled to −70° C. to 75° C., and further diluted with 115 mL of 14%triethylborane in tetrahydrofuran, 4 mL diethylmethoxyborane, 45 mLmethanol, and 8 mL acetic acid. Sodium borohydride (7 g) as a solutionin methanol (65 mL) containing 50% aqueous sodium hydroxide (3.2 g) isadded slowly at between −70° C. to −75° C. After the addition, thereaction mixture is warmed to 15° C. to 25° C., quenched by the additionof acetic acid, and concentrated by vacuum distillation—keeping thedistillate. The residue is diluted with methanol and concentrated byvacuum distillation—keeping this distillate and all subsequent onesseparate from the first one. The residue is dissolved in a mixture ofwater and ethyl acetate, the layers separated, and the organic layer isconcentrated by vacuum distillation. The residue is dissolved inmethanol and acetic acid and concentrated by vacuum distillation. Theresidue is dissolved in ethyl acetate and concentrated by vacuumdistillation resulting in crude [R-(R*,R*)-1,1-dimethylethyl6-cyano-3,5-dihydroxyhexanoate.

[0077] The cis:trans ratio was >50:1 as measured after conversion to (4Rcis and trans) 1,1-dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate according to theprocedure described herein in Step 3.

[0078] Step (b): Reusing Recovered Triethylborane andDiethylmethoxyborane Mixture

[0079] Following the procedure in Step (2)(b) as described in Method Aaffords [R-(R*,R*)-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.

[0080] Step (3): Preparation of (4R cis) 1,1-Dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate

[0081] Crude [R-(R*,R*)]-1,1-dimethylethyl6-cyano-3,5-dihydroxyhexanoate (about 150 moles) from Step (2) isdiluted with 100 kg of 2,2-dimethoxypropane and acidified with about 1 Lof methanesulfonic acid. The reaction is quenched by the addition ofaqueous sodium bicarbonate solution and concentrated by vacuumdistillation. The residue is diluted with 150 L of hexane, and thelayers separated. The organic layer is washed with aqueous sodiumbicarbonate solution and cooled to 0° C.±10° C. to crystallize. Theproduct is collected by filtration and washed with cooled hexane, thendried affording 28.5 kg of (4R cis) 1,1-dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate.

EXAMPLE 2[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenol-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, calcium salt (2:1) (crystalline Form I)

[0082] Step (1): Preparation of (4R-cis)-1.1-dimethylethyl6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate

[0083] (4R-cis)1,1-Dimethylethyl6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate (Example 1) isconverted to the title compound using the methodology disclosed atColumn 49, Lines 16-43 of U.S. Pat. No. 5,003,080.

[0084] Step (2): Preparation of (4R-cis)-1,1-Dimethylethyl6-r2[2-(fluorophenyl)-5-(-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate

[0085] (4R-cis)-1,1-Dimethylethyl6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate is converted to thetitle compound using the methodology disclosed at Column 49, Lines 43-60of the U.S. Pat. No. 5,003,080.

[0086] Step (3): Preparation of(2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide

[0087] (4R-cis)-1,1-Dimethyl6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate is converted to thetitle compound using the methodology disclosed at Column 50, Lines 4-30of U.S. Pat. No. 5,003,080.

[0088] Step (4): Preparation of[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, calcium salt (2:1) (crystalline Form I)

[0089](2R-trans)-5-(4-Fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamideis converted to the title compound using the methodology disclosed incopending U.S. patent application Ser. No. 08/945,812.

1. A process for the preparation of a compound of Formula I

wherein R is alkyl, NC—CH₂—, PG—O—CH₂—wherein PG is a protecting group,

R¹ is alkyl, or —CH₂—CO₂R⁶ wherein R⁶ is alkyl; which comprises: Step(a) treating a compound of Formula II

 or a compound of Formula III

 wherein R and R¹ are as defined above with a trialkylborane ordialkylalkoxyborane or a mixture of a trialkylborane and adialkylalkoxyborane in a solvent; Step (b) adding an alkali metalhydride at about −110° C. to about −50° C.; Step (c) concentrating thereaction by distillation to afford a compound of Formula I and adistillate containing alkylborane species; and Step (d) treatingadditional compound of Formula II or III with the distillate from Step(c) containing recovered alkylborane species, and repeating Steps (b)and (c) as desired to afford additional compound of Formula I.
 2. Theprocess according to claim 1 wherein the trialkylborane in Step (a) istriethylborane.
 3. The process according to claim 1 where in thedialkylalkoxyborane in Step (a) is diethylmethoxyborane.
 4. The processaccording to claim 1 wherein the solvent in Step (a) is selected fromthe group consisting of: tetrahydrofuran; methanol; and a mixture oftetrahydrofuran and methanol.
 5. The process according to claim 1wherein the distillation in Step (c) is a vacuum distillation.
 6. Theprocess according to claim 1 wherein PG is benzyl.
 7. The processaccording to claim 1 wherein the alkali metal hydride is sodiumborohydride.
 8. The process according to claim 1 for the preparation of[R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.
 9. Theprocess according to claim 1 for the preparation of the compound ofFormula Ia

wherein R⁶ is alkyl.
 10. A process for the preparation of a compound ofFormula I

wherein R is alkyl, NC—CH₂—, PG—O—CH₂—wherein PG is a protecting group,

R¹ is alkyl, or —CH₂—CO₂R⁶ wherein R⁶ is alkyl; which comprises: Step(a) treating a compound of Formula II

 or a compound of Formula III

 wherein R and R¹ are as defined above with a synergistic combination ofa trialkylborane and a dialkylalkoxyborane in a solvent; and Step (b)adding an alkali metal hydride at about −110° C. to about −50° C. toafford a compound of Formula I.
 11. The process according to claim 10wherein the trialkylborane in Step (a) is triethylborane.
 12. Theprocess according to claim 10 wherein the dialkylalkoxyborane in Step(a) is diethylmethoxyborane.
 13. The process according to claim 10wherein the solvent Step (a) is selected from the group consisting of:tetrahydrofuran; methanol; and a mixture of tetrahydrofuran andmethanol.
 14. The process according to claim 10 wherein PG is benzyl.15. The process according to claim 10 wherein the alkali metal hydrideis sodium borohydride.
 16. The process according to claim 10 for thepreparation of [R-(R*,R*)]-1,1-dimethylethyl6-cyano-3,5-dihydroxyhexanoate.
 17. The process according to claim 10for the preparation of the compound of Formula Ia

wherein R⁶ is alkyl.
 18. A synergistic combination comprising atrialkylborane and a dialkylalkoxyborane.
 19. A synergistic combinationcomprising about 1% to 99% by weight of a trialkylborane and about 99%to 1% by weight of a dialkylalkoxyborane.
 20. A synergistic combinationcomprising about 90% by weight of a trialkylborane and about 10% byweight of a dialkylalkoxyborane.
 21. A synergistic combinationcomprising triethylborane and diethylmethoxyborane.
 22. A method ofusing a synergistic combination comprising a trialkylborane and adialkylalkoxyborane for selectively reducing a beta-hydroxy ketone to acis-1,3-diol.
 23. The method according to claim 22 comprising about 1%to 99% by weight of a trialkylborane and about 99% to 1% by weight of adialkylalkoxyborane.
 24. The method according to claim 22 comprisingabout 90% by weight of a trialkylborane and about 10% by weight of adialkylalkoxyborane.
 25. The method according to claim 22 comprisingtriethylborane and diethylmethoxyborane.